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   Biotech / MedicalIndications -- obesity/erectile dysfunction


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From: scaram(o)uche1/20/2018 11:38:14 AM
   of 435
 
Br J Pharmacol. 2018 Jan 16. doi: 10.1111/bph.14147. [Epub ahead of print]

Single and combined effects of plant-derived (THC, CBD) and synthetic (WIN-55,212) cannabinoids on cognition and cannabinoid-associated withdrawal signs in mice.

Myers AM, Siegele PB, Foss JD, Tuma RF, Ward SJ.

Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.

BACKGROUND AND PURPOSE:
It has been suggested that the non-euphorogenic phytocannabinoid cannabidiol (CBD) can ameliorate adverse effects of delta-9-tetrahydrocannabinol (THC). We determined whether CBD ameliorates cognitive deficits and withdrawal signs induced by cannabinoid CB1/CB2 receptor agonists or produces these pharmacological effects on its own.

EXPERIMENTAL APPROACH:
The effects of THC or the CB1/CB2 receptor full agonist WIN55212 (WIN) alone, CBD alone, or their combination were tested across a range of doses. Cognitive effects were assessed in C57BL/6 mice in a conditional discrimination task and in the Barnes maze. Cannabinoid withdrawal signs were assessed following precipitated withdrawal by acute administration of the CB1 antagonist SR141716, the 5-HT1A receptor antagonist WAY100635, the TRPV1 receptor antagonist capsazepine, or the adenosine A2A receptor antagonist SCH58261.

KEY RESULTS:
THC produced significant motor and cognitive impairment in the Barnes maze task, and none of these deficits were attenuated by the addition of CBD. CBD alone did not impact cognitive performance. Precipitation of withdrawal signs by SR141716 occurred in mice chronically treated with THC or WIN, and these withdrawal signs were not attenuated by addition of chronic CBD. Chronic treatment with CBD alone did not induce withdrawal signs precipitated by SR141716 or WAY100635. Chronic CBD treatment also produced anxiolysis and this was not altered by attempting to precipitate withdrawal-induced anxiety with a range of antagonists.

CONCLUSIONS AND IMPLICATIONS:
These data suggest that CBD as a monotherapy may prove to be a safer pharmacological agent for the treatment of several disorders as compared with CB1 agonism alone or in combination with CBD.

Epilepsia. 2018 Jan;59(1):79-91. doi: 10.1111/epi.13950. Epub 2017 Nov 24.

Inhibition of monoacylglycerol lipase terminates diazepam-resistant status epilepticus in mice and its effects are potentiated by a ketogenic diet.

Terrone G1, Pauletti A1, Salamone A1, Rizzi M1, Villa BR1, Porcu L2, Sheehan MJ3, Guilmette E3, Butler CR4, Piro JR3, Samad TA3, Vezzani A1.

1
Department of Neuroscience, IRCCS-Mario Negri Institute for Pharmacological Research, Milano, Italy.
2
Department of Oncology, IRCCS-Mario Negri Institute for Pharmacological Research, Milano, Italy.
3
Internal Medicine Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, USA.
4
Medicinal Chemistry, Pfizer Worldwide Research & Development, Cambridge, MA, USA.

OBJECTIVE:
Status epilepticus (SE) is a life-threatening and commonly drug-refractory condition. Novel therapies are needed to rapidly terminate seizures to prevent mortality and morbidity. Monoacylglycerol lipase (MAGL) is the key enzyme responsible for the hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG) and a major contributor to the brain pool of arachidonic acid (AA). Inhibiting of monoacylglycerol lipase modulates synaptic activity and neuroinflammation, 2 mediators of excessive neuronal activation underlying seizures. We studied the effect of a potent and selective irreversible MAGL inhibitor, CPD-4645, on SE that was refractory to diazepam, its neuropathologic sequelae, and the mechanism underlying the drug's effects.

METHODS:
Diazepam-resistant SE was induced in adult mice fed with standard or ketogenic diet or in cannabinoid receptor type 1 (CB1) receptor knock-out mice. CPD-4645 (10 mg/kg, subcutaneously) or vehicle was dosed 1 and 7 h after status epilepticus onset in video-electroencephalography (EEG) recorded mice. At the end of SE, mice were examined in the novel object recognition test followed by neuronal cellloss analysis.

RESULTS:
CPD-4645 maximal plasma and brain concentrations were attained 0.5 h postinjection (half-life = 3.7 h) and elevated brain 2-AG levels by approximately 4-fold. CPD-4645 administered to standard diet-fed mice progressively reduced spike frequency during 3 h postinjection, thereby shortening SE duration by 47%. The drug immediately abrogated SE in ketogenic diet-fed mice. CPD-4645 rescued neuronal cell loss and cognitive deficit and reduced interleukin (IL)-1ß and cyclooxygenase 2 (COX-2) brain expression resulting from SE. The CPD-4645 effect on SE was similar in mice lacking CB1 receptors.

SIGNIFICANCE:
MAGL represents a novel therapeutic target for treating status epilepticus and improving its sequelae. CPD-4645 therapeutic effects appear to be predominantly mediated by modulation of neuroinflammation.

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From: scaram(o)uche6/8/2018 12:44:17 PM
   of 435
 
J Pain. 2018 May 2. pii: S1526-5900(18)30159-7. doi: 10.1016/j.jpain.2018.04.009. [Epub ahead of print]

Effects of cannabinoid type 2 receptor agonist AM1241 on morphine-induced antinociception, acute and chronic tolerance, and dependence in mice.

Zhang M1, Dong L1, Zou H2, Li J3, Li Q1, Wang G4, Li H5.

1
Department of Anesthesiology, Cancer Hospital of Harbin Medical University.
2
Department of Pain, Cancer Hospital of Harbin Medical University.
3
Department of Statistics, Harbin Medical University.
4
Department of Anesthesiology, Cancer Hospital of Harbin Medical University; Pain Research Institute of Heilongjiang Academy of Medical Sciences. Electronic address: wangguonian609cn@sohu.com.
5
Department of neurobiology, Harbin Medical University. Electronic address: lihl@hrbmu.edu.cn.

Morphine is a potent opioid analgesic used to alleviate moderate or severe pain but the development of drug tolerance and dependence limits its use in pain management. Previous studies showed that cannabinoid type 2 (CB2) receptor ligands may modulate opioid effects. However, there is no report of the effect of CB2 receptor agonist on acute morphine tolerance and physical dependence. We therefore investigated the effect of a CB2 receptor agonist (AM1241) on morphine-induced morphine tolerance and physical dependence in mice. Repeated coadministration of AM1241 (1 or 3mg/kg, intraperitoneally) and morphine (10mg/kg, subcutaneously) for 7 days increased mechanical paw withdrawal threshold in mice as measured by the von Frey filament test, and 3mg/kg AM1241 in combination with morphine increased thermal paw withdrawal latency as measured by the hot-plate test. Combination with 3 mg/kg AM1241 and morphine increased acute morphine antinociception. Coadministration of 1 or 3 mg/kg AM1241 and morphine reduced acute morphine tolerance, and 3 mg/kg AM1241 reduced chronic morphine tolerance. Coadministration of 1 or 3 mg/kg AM1241 and morphine reduced naloxone-precipitated withdrawal jumping, but not diarrhea. Coadministration of AM1241 and morphine did not inhibit spontaneous locomotor activity. Pretreatment with 3 mg/kg AM1241 reduced the chronic morphine-induced Iba1 expression in spinal cord. Coadministration of AM1241 (3 mg/kg) reduced the production of IL-1ß, TNF-aand IL-6 induced by chronic and acute morphine treatment. Our findings suggest that coadministration of the CB2 receptor agonist and morphine could increase morphine antinociception and reduce morphine tolerance and physical dependence in mice.

PERSPECTIVE:
Combination of a CB2 agonist and morphine may provide a new strategy for better treatment of acute and chronic pain, and prevention of opioid tolerance and dependence. This may also provide a clue for the treatment of opioid tolerance and dependence in clinic.

CNS Drugs. 2018 May 7. doi: 10.1007/s40263-018-0515-7. [Epub ahead of print]

Activation of the Cannabinoid Type 2 Receptor by a Novel Indazole Derivative Normalizes the Survival Pattern of Lymphoblasts from Patients with Late-Onset Alzheimer's Disease.

Del Cerro P1, Alquézar C1, Bartolomé F1,2,3, González-Naranjo P4, Pérez C4, Carro E2,3, Páez JA4, Campillo NE5, Martín-Requero Á6,7.

1
Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain.
2
Neurodegenerative Disorders Group, Instituto de Investigacion Hospital, 12 de Octubre, Madrid, Spain.
3
CIBER de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
4
Instituto de Química Médica (CSIC), Madrid, Spain.
5
Department of Chemical and Physical Biology, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain. nuria.campillo@csic.es.
6
Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain. amrequero@cib.csic.es.
7
CIBER de Enfermedades Raras (CIBERER), Madrid, Spain. amrequero@cib.csic.es.

BACKGROUND:
Alzheimer's disease is a multifactorial disorder for which there is no disease-modifying treatment yet. CB2 receptors have emerged as a promising therapeutic target for Alzheimer's disease because they are expressed in neuronal and glial cells and their activation has no psychoactive effects.

OBJECTIVE:
The aim of this study was to investigate whether activation of the CB2 receptor would restore the aberrant enhanced proliferative activity characteristic of immortalized lymphocytes from patients with late-onset Alzheimer's disease. It is assumed that cell-cycle dysfunction occurs in both peripheral cells and neurons in patients with Alzheimer's disease, contributing to the instigation of the disease.

METHODS:
Lymphoblastoid cell lines from patients with Alzheimer's disease and age-matched control individuals were treated with a new, in-house-designed dual drug PGN33, which behaves as a CB2 agonist and butyrylcholinesterase inhibitor. We analyzed the effects of this compound on the rate of cell proliferation and levels of key regulatory proteins. In addition, we investigated the potential neuroprotective action of PGN33 in ß-amyloid-treated neuronal cells.

RESULTS:
We report here that PGN33 normalized the increased proliferative activity of Alzheimer's disease lymphoblasts. The compound blunted the calmodulin-dependent overactivation of the PI3K/Akt pathway, by restoring the cyclin-dependent kinase inhibitor p27 levels, which in turn reduced the activity of the cyclin-dependent kinase/pRb cascade. Moreover, this CB2 agonist prevented ß-amyloid-induced cell death in neuronal cells.

CONCLUSION:
Our results suggest that the activation of CB2 receptors could be considered a useful therapeutic approach for Alzheimer's disease.

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From: scaram(o)uche8/21/2018 12:42:36 PM
   of 435
 
GPCRs: Peeling The Onion Some More

blogs.sciencemag.org

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From: scaram(o)uche9/17/2018 3:04:44 PM
   of 435
 
J Med Chem. 2018 Sep 10. doi: 10.1021/acs.jmedchem.8b00611. [Epub ahead of print]

(R)-N-(1-Methyl-2-hydroxyethyl)-13-(S)-methyl-arachidonamide (AMG315): A Novel Chiral Potent Endocannabinoid Ligand with Stability to Metabolizing Enzymes.

Liu Y, Ji L, Eno M, Kudalkar S, Li A, Schimpgen M, Benchama O, Morales P, Xu S, Hurst DP, Wu S, Mohammad KA, Wood JT, Zvonok N, Papahatjis D, Zhou H, Honrao C, Mackie K, Reggio PH, Hohmann A, Marnett LJ, Makriyannis A, Nikas SP.

The synthesis of potent metabolically stable endocannabinoids is challenging. Here we report a chiral arachidonoyl ethanolamide (AEA) analog, namely, (13S, 1'R)-dimethylanandamide (AMG315, 3a) a high affinity ligand for the CB1 receptor (Ki of 7.8 ± 1.4 nM) that behaves as a potent CB1 agonist in vitro (EC50 = 0.6 ± 0.2 nM). (13S, 1'R)-dimethylanandamide is the first potent AEA analog with significant stability for all endocannabinoid hydrolyzing enzymes as well as the oxidative enzymes COX-2. When tested in vivo using the CFA-induced inflammatory pain model 3a behaved as a more potent analgesic when compared to endogenous AEA or its hydrolytically stable analog AM356. This novel analog will serve as a very useful endocannabinoid probe.

Biochem Pharmacol. 2018 Sep 5. pii: S0006-2952(18)30382-4. doi: 10.1016/j.bcp.2018.08.046. [Epub ahead of print]

Cannabidiol skews biased agonism at cannabinoid CB1 and CB2 receptors with smaller effect in CB1-CB2 heteroreceptor complexes.

Navarro G1, Reyes-Resina I2, Rivas-Santisteban R2, Sánchez de Medina V3, Morales P4, Casano S3, Ferreiro-Vera C3, Lillo A5, Aguinaga D5, Jagerovic N4, Nadal X6, Franco R7.
1
Molecular Neurobiology laboratory, Department of Biochemistry and Physiology, Universitat de Barcelona. Barcelona, Spain; Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III. Madrid, Spain.
2
Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III. Madrid, Spain; Molecular Neurobiology laboratory, Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona. Barcelona, Spain.
3
Phytoplant Research S.L., Córdoba, Spain.
4
Instituto de Química Médica, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
5
Molecular Neurobiology laboratory, Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona. Barcelona, Spain.
6
Phytoplant Research S.L., Córdoba, Spain. Electronic address: x.nadal@phytoplant.es.
7
Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III. Madrid, Spain; Molecular Neurobiology laboratory, Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona. Barcelona, Spain.

Currently, biased agonism is at the center stage of drug development approaches. We analyzed effects of a battery of cannabinoids plus/minus cannabidiol (CBD) in four functional parameters (cAMP levels, phosphorylation of extracellular signal-regulated kinases (ERK1/2), ß-arrestin recruitment and label-free/DMR) in HEK-293T cells expressing cannabinoid receptors, CB1 or CB2, or CB1-CB2 heteroreceptor complexes. In all cases two natural agonists plus two selective synthetic agonists were used. Furthermore, the effect of cannabidiol, at a dose (100 nM) that does not allow significant binding to the orthosteric center of either receptor, was measured. From the huge amount of generated data, we would like to highlight that the two psychotropic molecules (?9-tetrahydrocannabinol/THC and CP-55940) showed similar bias in CB1R and that the bias of THC was particularly relevant toward MAPK pathway. Furthermore, THC did not activate the Gi protein coupled to CB2R. Interestingly, the biased agonism was reduced when assays were performed in cells expressing the two receptors, thus suggesting that the heteromer allows less functional selectivity. In terms of cannabidiol action, the phytocannabinoid altered the functional responses, likely by allosteric means, and modified potency, agonist IC50/EC50 values and biased agonism in qualitative and/or quantitative different ways depending on the agonist. The effect of cannabidiol on anandamide actions on both cannabinoid receptors was particularly noteworthy as was significantly different from that of other compounds. Results are a compendium of data on biased agonism on cannabinoid receptors in the absence and presence of cannabidiol. In addition, for the first time, GPCR biased agonism is characterized in an heteromeric context.

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From: scaram(o)uche9/21/2018 3:22:02 PM
   of 435
 
Just parking some links related to Jenrin Discovery/Corbus and their lead molecule.....

ncbi.nlm.nih.gov

ncbi.nlm.nih.gov

Jenrin has been around for years, wouldn't be surprised if there are related pointers in this thread.

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From: scaram(o)uche9/25/2018 3:29:06 PM
   of 435
 
Pain. 2018 Aug 27. doi: 10.1097/j.pain.0000000000001386. [Epub ahead of print]

Cannabidiol modulates serotonergic transmission and prevents allodynia and anxiety-like behavior in a model of neuropathic pain.

De Gregorio D1,2, McLaughlin RJ3,2, Posa L1,4, Ochoa-Sanchez R1, Enns J1, Lopez-Canul M1, Aboud M1, Maione S5, Comai S1,6, Gobbi G1,4.

1
Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal (QC), Canada.
2
Equal author contribution.
3
Department of Integrative Physiology and Neuroscience, Washington State University, Pullman (WA) USA.
4
Alan Edwards Centre for Research on Pain, McGill University, Montreal (QC), Canada.
5
Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.
6
San Raffaele Scientific Institute and Vita Salute University, Milan, Italy.

Clinical studies indicate that cannabidiol (CBD), the primary non-addictive component of cannabis that interacts with the serotonin (5-HT) 1A receptor, may possess analgesic and anxiolytic effects. However, its effects on 5-HT neuronal activity, as well as its impact in models of neuropathic pain are unknown. First, using in-vivo single unit extracellular recordings in rats, we demonstrated that acute intravenous (i.v.) increasing doses of CBD (0.1-1.0 mg/kg) decreased the firing rate of 5-HT neurons in the dorsal raphe nucleus (DRN), which was prevented by administration of the 5-HT1A antagonist WAY 100635 (0.3 mg/kg, i.v.) and the TRPV1 antagonist capsazepine (1 mg/kg, i.v.) but not by the CB1 receptor antagonist AM 251 (1 mg/kg, i.v.). Repeated treatment with CBD (5 mg/kg/day, subcutaneously, s.c, for 7 days) increased 5-HT firing via desensitization of 5-HT1A receptors. Rats subjected to the spared nerve injury (SNI) model for 24 days showed decreased 5-HT firing activity, mechanical allodynia, and increased anxiety-like behavior in the elevated plus maze (EPMT), open field (OFT), and novelty suppressed feeding tests (NSFT). Seven days of treatment with CBD reduced mechanical allodynia, decreased anxiety-like behavior, and normalized 5-HT activity. Anti-allodynic effects of CBD were fully prevented by capsazepine (10 mg/kg/day, s.c., for 7 days) and partially prevented by WAY 100635 (2 mg/kg/day, s.c., for 7 days), while the anxiolytic effect was blocked only by WAY. Overall, repeated treatment with low-dose CBD induces analgesia predominantly via TRPV1 activation, reduces anxiety via 5-HT1A receptor activation, and rescues impaired 5-HT neurotransmission under neuropathic pain conditions.

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From: scaram(o)uche9/29/2018 2:08:32 PM
   of 435
 
Psychopharmacology (Berl). 2018 Sep 24. doi: 10.1007/s00213-018-5020-7. [Epub ahead of print]

Effects of fatty acid amide hydrolase inhibitor URB597 in a rat model of trauma-induced long-term anxiety.

Danandeh A1, Vozella V1, Lim J1,2, Oveisi F1, Ramirez GL1, Mears D3,4, Wynn G4, Piomelli D5,6,7.

1
Department of Anatomy and Neurobiology, University of California, 3101 Gillespie NRF, Irvine, CA, 92697-4625, USA.
2
Department of Molecular & Cellular Biology, The University of Arizona, Tucson, AZ, USA.
3
Department of Anatomy, Physiology, and Genetics, Uniformed Service University of the Health Sciences, Bethesda, MD, USA.
4
Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Service University of the Health Sciences, Bethesda, MD, USA.
5
Department of Anatomy and Neurobiology, University of California, 3101 Gillespie NRF, Irvine, CA, 92697-4625, USA. piomelli@uci.edu.
6
Department of Pharmacology, University of California, Irvine, CA, 92697, USA. piomelli@uci.edu.
7
Department of Biological Chemistry, University of California, Irvine, CA, 92697, USA. piomelli@uci.edu.

RATIONALE:
The endocannabinoid neurotransmitter, anandamide, has been implicated in the central modulation of stress responses. Previous animal experiments have shown that inhibitors of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), enhance the ability to cope with acute and chronic stress.

OBJECTIVES:
Here, we investigated the effects of the globally active FAAH inhibitor URB597 in a rat model of predator stress-induced long-term anxiety.

RESULTS:
Rats exposed to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a chemical constituent of fox feces, developed a persistent anxiety-like state, which was assessed 7 days after exposure using the elevated plus maze (EPM) test. Systemic administration of URB597 [0.03-0.1-0.3 mg/kg, intraperitoneal (ip)] 2 h before testing suppressed TMT-induced behaviors with a median effective dose (IC50) of 0.075 mg/kg. This effect was strongly correlated with inhibition of brain FAAH activity (r2?=?1.0) and was accompanied by increased brain levels of three FAAH substrates: the endocannabinoid anandamide and the endogenous peroxisome proliferator-activated receptor-a (PPAR-a) agonists, oleoylethanolamide (OEA), and palmitoylethanolamide (PEA). The anxiolytic-like effects of URB597 were blocked by co-administration of the CB1 receptor antagonist rimonabant (1 mg/kg, ip), but not of the PPAR-a antagonist GW6471 (1 mg/kg, ip). Finally, when administered 18 h after TMT exposure (i.e., 6 days before the EPM test), URB597 (0.3 mg/kg, ip) prevented the consolidation of anxiety-like behavior in a CB1-dependent manner.

CONCLUSIONS:
The results support the hypothesis that anandamide-mediated signaling at CB1 receptors serves an important regulatory function in the stress response, and confirm that FAAH inhibition may offer a potential therapeutic strategy for post-traumatic stress disorder.

Neurotox Res. 2018 Aug 24. doi: 10.1007/s12640-018-9944-9. [Epub ahead of print]

Neuroprotective Action of the CB1/2 Receptor Agonist, WIN 55,212-2, against DMSO but Not Phenobarbital-Induced Neurotoxicity in Immature Rats.

Huizenga MN1, Forcelli PA2,3,4.

1
Department of Pharmacology and Physiology, Georgetown University, Washington, DC, 20007, USA.
2
Department of Pharmacology and Physiology, Georgetown University, Washington, DC, 20007, USA. paf22@georgetown.edu.
3
Department of Neuroscience, Georgetown University, Washington, DC, USA. paf22@georgetown.edu.
4
Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC, USA. paf22@georgetown.edu.

The developing brain is uniquely susceptible to drug-induced increases in programmed cell death or apoptosis. Many compounds, including anticonvulsant drugs, anesthetic agents, and ethanol, when administered in a narrow postnatal window in rodents, result in increased pruning of neurons. Here, we report that dimethyl sulfoxide (DMSO) triggers widespread neurodegeneration in the immature (postnatal day, P7) rat brain, an effect consistent with a prior report in neonatal mice. We found that the synthetic cannabinoid receptor agonist WIN 55,212-2 (WIN) exerts a neuroprotective effect against DMSO-induced cell death. We extended these findings to determine if WIN is neuroprotective against another drug class known to increase developmental cell death, namely antiseizure drugs. The antiseizure drug phenobarbital (PB) remains the primary treatment for neonatal seizures, despite significantly increasing cell death in the developing rodent brain. WIN exerts antiseizure effects in immature rodent seizure models, but increases the toxicity associated with neonatal ethanol exposure. We thus sought to determine if WIN would protect against or exacerbate PB-induced cell death. Unlike either the prior report with ethanol or our present findings with DMSO, WIN was largely without effect on PB-induced cell death. WIN alone did not increase cell death over levels observed in vehicle-treated rats. These data suggest that WIN has a favorable safety profile in the developing brain and could potentially serve as an adjunct therapy with phenobarbital (albeit one that does not attenuate PB-induced toxicity).

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From: scaram(o)uche9/29/2018 3:50:43 PM
   of 435
 
Biochem Pharmacol. 2018 Aug 7. pii: S0006-2952(18)30327-7. doi: 10.1016/j.bcp.2018.08.007. [Epub ahead of print]

Genetic deletion of CB1 cannabinoid receptors exacerbates the Alzheimer-like symptoms in a transgenic animal model.

Aso E1, Andrés-Benito P2, Ferrer I2.

1
Department of Pathology and Experimental Therapeutics, University of Barcelona-IDIBELL, L'Hospitalet de Llobregat, Spain; CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain. Electronic address: ester.aso@ub.edu.
2
Department of Pathology and Experimental Therapeutics, University of Barcelona-IDIBELL, L'Hospitalet de Llobregat, Spain; CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain.

Activating CB1 cannabinoid receptor has been demonstrated to produce certain therapeutic effects in animal models of Alzheimer's disease (AD). In this study, we evaluated the specific contribution of CB1 receptor to the progression of AD-like pathology in double transgenic APP/PS1 mice. A new mouse strain was generated by crossing APP/PS1 transgenic mice with CB1 knockout mice. Genetic deletion of CB1 drastically reduced the survival of APP/PS1 mice. In spite that CB1 mutant mice bearing the APP/PS1 transgene developed normally, they suddenly died within the first two months of life likely due to spontaneous seizures. This increased mortality could be related to an imbalance in the excitatory/inhibitory transmission in the hippocampus as suggested by the reduced density of inhibitory parvalbumin positive neurons observed in APP/PS1 mice lacking CB1 receptor at 7?weeks of age. We also evaluated the AD-like phenotype of APP/PS1 mice heterozygous for the CB1 deletion at 3 and 6?months of age. The memory impairment associated to APP/PS1 transgene was accelerated in these mice. Neither the soluble levels of Aß or the density of Aß plaques were modified in APP/PS1 mice heterozygous for CB1 deletion at any age. However, the reduction in CB1 receptor expression decreased the levels of PSD-95 protein in APP/PS1 mice, suggesting a synaptic dysfunction in these animals that could account for the acceleration of the memory impairment observed. In summary, our results suggest a crucial role for CB1 receptor in the progression of AD-related pathological events.

And that's just the plot-twist trailer, movie will be out in three weeks.

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From: scaram(o)uche11/6/2018 11:30:33 AM
   of 435
 
Excellent, just excellent!!......

>> THC feels different when combined it with cannabidiol, or CBD, another naturally occurring compound in cannabis, but the reasons aren’t fully known. It’s called the entourage effect: THC, like a rock star, only reaches its full potential when it rolls with a crew <<

wired.com

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To: scaram(o)uche who wrote (381)1/17/2019 9:02:09 AM
From: scaram(o)uche
   of 435
 
Well....... PRs of course often don't tell entire story, but second generation molecule is incredibly effective, second cohort of a phase II study. PR suggests no safety signal....

zafgen.gcs-web.com

Don't know if company has described difference between beloranib and 1061, described off target tox for beloranib. If it has, this is worth watching.

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